Our long-term goal is to advance the understanding, at the molecular level, of the pathogenicity and epidemiology of uropathogenic Escherichia coli strains to better target treatment and prophylaxis of urinary tract infections (UTIs), reduce antibiotic resistance, and provide information on possible targets for vaccines and antibiotics. The most common cause of fluoroquinolone and multi-drug resistant UTIs are two E. coli strains that comprise clonal groups ST131-H30 and ST1193. Those pandemic multi-drug resistant strains (PMDR) have emerged 1-2 decades ago, are globally spread and, combined, are responsible for 60- 80% of the antibiotic-resistant UTIs. At the same time, PMDR appears to be able persisting for many months, possibly years in the gut and urinary bladder of healthy women, without them having symptoms of UTI or taking antibiotics. The objective of the proposed work is to investigate in detail the frequency, patterns and clinical risks of asymptomatic gut and bladder carriage of PMDR, identify possible means of the carriers de-colonization and compare on a genome-wide scale the PMDR isolates from women without and with UTI. Our preliminary data support that we can investigate sizeable samples of fecal and urine samples, establish the clonal identity of fresh isolates, and determine genome-wide the pathogenicity-adaptive genetic changes. We will determine how mutational changes (single nucleotide polymorphisms, small insertions/deletions, etc.) and horizontal gene transfer contribute to the urovirulence of PMDR. For this, we will employ a population genomics- based analysis to trace the mutations and gene transfer, followed by assessment of the functional significance of the representative positively selected loci in PMDR. practical terms, accomplishment of the proposed studies will advance at the molecular level our understanding of the ecology, pathogenicity, and epidemiology of antibiotic-resistant uropathogenic E. coli and will provide information on possible targets for vaccines, antibiotics, or other therapeutics.

Public Health Relevance

The most common cause of multi-drug resistant urinary tract infections (UTIs) are two Escherichia coli strains, that at the same time appears to be able persisting for a long time in the gut and bladder of healthy women, without symptoms of UTI or taking antibiotics. The objective of the proposed work is to investigate in detail the frequency of gut and bladder carriage by these two strains, identify possible means of the carriers de-colonization and compare on a genome-wide scale the E. coli strains from women without and with UTI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI106007-06
Application #
9997719
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ernst, Nancy L
Project Start
2013-11-19
Project End
2025-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Roer, Louise; Tchesnokova, Veronika; Alles√łe, Rosa et al. (2017) Development of a Web Tool for Escherichia coli Subtyping Based on fimH Alleles. J Clin Microbiol 55:2538-2543
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Leatham-Jensen, Mary P; Mokszycki, Matthew E; Rowley, David C et al. (2016) Uropathogenic Escherichia coli Metabolite-Dependent Quiescence and Persistence May Explain Antibiotic Tolerance during Urinary Tract Infection. mSphere 1:
Johnson, Timothy J; Aziz, Maliha; Liu, Cindy M et al. (2016) Complete Genome Sequence of a CTX-M-15-Producing Escherichia coli Strain from the H30Rx Subclone of Sequence Type 131 from a Patient with Recurrent Urinary Tract Infections, Closely Related to a Lethal Urosepsis Isolate from the Patient's Sister. Genome Announc 4:
Tchesnokova, Veronika; Avagyan, Hovhannes; Billig, Mariya et al. (2016) A Novel 7-Single Nucleotide Polymorphism-Based Clonotyping Test Allows Rapid Prediction of Antimicrobial Susceptibility of Extraintestinal Escherichia coli Directly From Urine Specimens. Open Forum Infect Dis 3:ofw002

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